Infections and inflammation have now emerged as important risk factors for cardiovascular diseases1, the major cause of death in Western societies. Indeed, elevation of inflammatory markers in the serum predicts the prognosis of patients with coronary heart diseases2 and dilated cardiomyopathy3,4. In particular, dilated cardiomyopathy, the commonest cause of heart failure in young patients5,6,7, has been linked to autoimmune responses following infection with cardiotropic viruses, since many of these patients display autoantibodies against heart proteins6,7,8. Similar autoimmune mechanisms have been implicated in heart failure after infection with the protozoan Trypanozoma cruzii7. Autoimmunity is characterized by a number of classic criteria24, including defined self-antigens, organ specificity and autoreactive T-cells and/or autoantibodies that can transfer disease.
Animal models support the idea that microbial infection can trigger autoimmune responses against heart tissue7. Mice with defined genetic backgrounds develop prolonged myocarditis, with autoreactive T-cells, after Coxsackie B37 and Trypanozoma cruzii9 infection. In the same mouse strains, immunization with heart specific α-myosin or a sixteen amino acid, α-myosin-heavy-chain epitope together with strong adjuvant induces T-cell mediated myocarditis7,10,11. Importantly, it has been shown that hearts from normal mice contain large numbers of tissue-resident cells presenting endogenous heart specific peptides12. It is not known, however, whether dendritic cells presenting endogenous self-antigens might contribute to autoimmune heart disease and possibly heart failure. What is needed is an animal model that allow researchers to study the mechanisms by which cardiomyopathy develops in young patients and, more importantly, to identify compounds that interfere with that development.
Dendritic cells are key players in the induction of antigen-specific immune responses13,14,15 as well as of immunotolerance16,17. Immature dendritic cells reside in the peripheral tissues, where they actively sample their environment by endocytosis and macropinocytosis. Upon encountering a pathogen, they undergo a developmental program called dendritic cell maturation, which includes induction of costimulatory activity, antigen processing, increased MHC molecule expression, and migration to the lymph node, where they can prime naïve antigen-specific T cells13. Dendritic cells also process endogenous antigens from debris and dead cells13,15,16. It has therefore been proposed that dendritic cells might trigger autoreactive T-cells if activated appropriately13,17. There is increasing evidence that processing of dying cells and self-tissue, in the absence of appropriate stimulation, renders dendritic cells tolerogenic for CD8+ T-cell18- and CD4+ T-cell19-mediated immune responses. Current research has therefore focused on the role of dendritic cells in maintaining self-tolerance. Some research has indicated that dendritic cells can induce organ-specific inflammation in a transgenic model of viral antigen expression20, but there is still only indirect evidence that activated dendritic cells can induce autoimmunity to self-antigens13,21. Moreover, it has never been shown that dendritic cells pulsed with self-proteins are indeed capable of inducing autoimmunity in “naïve” mice. Dendritic cells express multiple Toll-like receptors and therefore these cells are pivotally positioned at the interface of adaptive and innate immunity21. The innate immune system is a universal and ancient form of host defense against infection21.
Dendritic cells are comprised of a heterogeneous cell population with a widespread tissue distribution. The use of dendritic cells for research and more practical applications has been limited due to the low frequency of dendritic cells in peripheral blood, the limited accessibility of lymphoid organs and the dendritic cells' terminal state of differentiation. The number of dendritic cells necessary for activation by current methods is of the order of at least 1×106 cells. What is needed is a method for dendrite cell activation that requires fewer cells, of the order of 5×104 to 2×105 cells.
Research has shown that the immune system is capable of killing tumor cells to some extent; tumors nevertheless often prevail. Various methods for immunotherapy to treat cancers have been suggested but a therapeutic method that successfully elicits an effective and specific immunotherapeutic response against a target tumor has not yet been realized. What is needed is a method that consistently and specifically generates an immune response to a tumor in vivo, resulting in the eradication of the tumor.
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